Adoptive T-cell therapy, CAR T cells

Adoptive T-cell therapy is somewhat similar to the genetically modified tumor vaccine. However, rather than harvesting, culturing and genetically modifying tumor cells, adoptive T-cell therapy uses T cells harvested from a patient’s peripheral blood or tumor infiltrate. These cells are cultured and manipulated in vitro, then reinfused into the patient to induce an anti-tumor immune response (Figure 3). Chimeric antigen receptor (CAR) T-cell therapy is an example of adoptive T-cell therapy in which the harvested T cells are altered to express specific surface antigen receptors—CARs. Once the modified T cells are reinfused, the CARs attach to the antigens on tumor cells.

Figure 3. Adoptive T-cell therapy.

Martin Pule, MD, PhD, describes adoptive T-cell therapy.

Neoantigens

One of the roadblocks to some of the cellular therapies, resulting in limited efficacy, is the ability for tumor cells to evade even targeted agents because the antigens expressed on their cell surfaces are ultimately recognized as self antigens by the immune system; this process of evasion is called immune tolerance. A new area of research focuses on targeting tumor-specific antigens, or neoantigens, that result from genetic mutations during the process of malignant transformation. Because these antigens are the products of genetic mutation, they should not be recognized as self-antigens, which would allow for a much more robust treatment response.

Immune Microenvironment (IDO inhibitors, CSF1R, VEGF)

Tumor cells exist in a microenvironment that includes immune cells, signaling molecules, and a rich vascular network that promotes tumor growth and is fueled by the other components of the tumor microenvironment. Targeting and inhibition of angiogenesis-promoting cell surface proteins and protein receptors such as vascular endothelial growth factor (VEGF) and colony stimulating factor 1 receptor (CSF1R) can slow tumor cell growth and progression by interrupting the vascular supply that feeds tumor cells.

Another member of the tumor immune microenvironment is indoleamine-2,3-dioxygenase (IDO), an intracellular enzyme with an immunosuppressive effect that allows tumor cells to escape detection by the immune system. IDO is expressed by certain antigen-presenting cells, such as dendritic cells, and is also expressed (variably) by tumor cells. Current research is focused on the inhibition of IDO pathways, circumventing the immune tolerance mechanism of immune evasion.

Robert Andtbacka, MD, discusses some of the new areas of immuno-oncologic therapy research.

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